Langerhans cells (LCs) of the epidermis are critical antigen presenting cells required for initiating a protective immune response against pathogens that invade the skin. However, they may also play a detrimental role by triggering graft-versus-host disease (GVHD) in recipients of allogeneic bone marrow transplants (BMT). Whereas host LCs are rapidly replaced by donor derived cells after allogeneic BMT in mice, following transplantation with T cell depleted BM, host LCs are not replaced and GVHD does not occur. We hypothesize that in recipients of BM allografts that contain sufficient T cells, these cells infiltrate the skin where they attack resident LCs and induce the release of cytokines and chemokines that attract donor-derived LCs. In this project we will identify the cells and molecules responsible for these phenomena. In addition, we will directly assess the ability of LCs to stimulate and act as targets for skin GVHD, determine if regulatory T cells can affect LC chimerism and determine if GVHD can be prevented by selectively depleting host LCs or blocking the trafficking of allogeneic T cells to the skin. Finally, in patients who receive allogeneic progenitor cell transplants we will determine if there is a correlation between LC replacement and skin GVHD. Finally, we will determine if GVHD can be prevented or treated in murine models by selectively blocking the trafficking of allogeneic T cells to the skin. The results of these studies should provide fundamental information about the life cycle of LCs and, in keeping with the theme of this program project, possibly lead to safer and more effective ways of using allogeneic stem cells to reconstitute the immune systems of patients with life threatening diseases.